Maria Grazia Muoio1,2, Marianna Talia2, Rosamaria Lappano2, Andrew H Sims3, Veronica Vella1, Francesca Cirillo2, Livia Manzella4,5, Marika Giuliano1, Marcello Maggiolini2, Antonino Belfiore1, Ernestina Marianna De Francesco1. 1. Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, 95122 Catania, Italy. 2. Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy. 3. Applied Bioinformatics of Cancer, University of Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, Crewe Road South, Edinburgh EH4 2XU, UK. 4. Center of Experimental Oncology and Hematology, A.O.U. Policlinico Vittorio Emanuele, 95122 Catania, Italy. 5. Department of Clinical and Experimental Medicine, University of Catania, 95122 Catania, Italy.
Abstract
BACKGROUND: Breast cancer (BC) mortality is increased among obese and diabetic patients. Both obesity and diabetes are associated with dysregulation of both the IGF-1R and the RAGE (Receptor for Advanced Glycation End Products) pathways, which contribute to complications of these disorders. The alarmin S100A7, signaling through the receptor RAGE, prompts angiogenesis, inflammation, and BC progression. METHODS: We performed bioinformatic analysis of BC gene expression datasets from published studies. We then used Estrogen Receptor (ER)-positive BC cells, CRISPR-mediated IGF-1R KO BC cells, and isogenic S100A7-transduced BC cells to investigate the role of IGF-1/IGF-1R in the regulation of S100A7 expression and tumor angiogenesis. To this aim, we also used gene silencing and pharmacological inhibitors, and we performed gene expression and promoter studies, western blotting analysis, ChIP and ELISA assays, endothelial cell proliferation and tube formation assay. RESULTS: S100A7 expression correlates with worse prognostic outcomes in human BCs. In BC cells, the IGF-1/IGF-1R signaling engages STAT3 activation and its recruitment to the S100A7 promoter toward S100A7 increase. In human vascular endothelial cells, S100A7 activates RAGE signaling and prompts angiogenic effects. CONCLUSIONS: In ER-positive BCs the IGF-1 dependent activation of the S100A7/RAGE signaling in adjacent endothelial cells may serve as a previously unidentified angiocrine effector. Targeting S100A7 may pave the way for a better control of BC, particularly in conditions of unopposed activation of the IGF-1/IGF-1R axis.
BACKGROUND:Breast cancer (BC) mortality is increased among obese and diabeticpatients. Both obesity and diabetes are associated with dysregulation of both the IGF-1R and the RAGE (Receptor for Advanced Glycation End Products) pathways, which contribute to complications of these disorders. The alarmin S100A7, signaling through the receptor RAGE, prompts angiogenesis, inflammation, and BC progression. METHODS: We performed bioinformatic analysis of BC gene expression datasets from published studies. We then used Estrogen Receptor (ER)-positive BC cells, CRISPR-mediated IGF-1R KO BC cells, and isogenic S100A7-transduced BC cells to investigate the role of IGF-1/IGF-1R in the regulation of S100A7 expression and tumor angiogenesis. To this aim, we also used gene silencing and pharmacological inhibitors, and we performed gene expression and promoter studies, western blotting analysis, ChIP and ELISA assays, endothelial cell proliferation and tube formation assay. RESULTS:S100A7 expression correlates with worse prognostic outcomes in human BCs. In BC cells, the IGF-1/IGF-1R signaling engages STAT3 activation and its recruitment to the S100A7 promoter toward S100A7 increase. In human vascular endothelial cells, S100A7 activates RAGE signaling and prompts angiogenic effects. CONCLUSIONS: In ER-positive BCs the IGF-1 dependent activation of the S100A7/RAGE signaling in adjacent endothelial cells may serve as a previously unidentified angiocrine effector. Targeting S100A7 may pave the way for a better control of BC, particularly in conditions of unopposed activation of the IGF-1/IGF-1R axis.
Authors: Mohd W Nasser; Nissar Ahmad Wani; Dinesh K Ahirwar; Catherine A Powell; Janani Ravi; Mohamad Elbaz; Helong Zhao; Laura Padilla; Xiaoli Zhang; Konstantin Shilo; Michael Ostrowski; Charles Shapiro; William E Carson; Ramesh K Ganju Journal: Cancer Res Date: 2015-01-08 Impact factor: 12.701
Authors: Peter Kubatka; Alena Mazurakova; Marek Samec; Lenka Koklesova; Kevin Zhai; Raghad Al-Ishaq; Karol Kajo; Kamil Biringer; Desanka Vybohova; Aranka Brockmueller; Martin Pec; Mehdi Shakibaei; Frank A Giordano; Dietrich Büsselberg; Olga Golubnitschaja Journal: EPMA J Date: 2021-10-06 Impact factor: 6.543